Craniosynostosis is a common malformation, defined as the premature fusion of one or more calvarial sutures. It has a birth prevalence of 3 to 5 per 10,000 live births in all racial populations. In more than 85% of cases, craniosynostosis is nonsyndromic (i.e., occurs as an isolated anomaly), and approximately half of these cases involve the sagittal suture. Nonsyndromic craniosynostosis (NSC) is a heterogeneous condition caused by environmental and genetic factors. Although substantial advances have been made in understanding the clinical and molecular aspects of syndromic craniosynostosis caused by single gene mutations, knowledge of associated phenotypic variability of NSC, outcome, genetics, and modifiable risk factors is limited. Population-based analysis of the clinical features, craniofacial anthropometric profiles, and medical and surgical outcomes of cases with NSC evaluated under a standardized protocol will further characterize these phenotypes. Clinically homogeneous groups of patients with isolated NSC will be useful in identifying causative genes by candidate gene association analysis. We will enroll nonsyndromic cases of sagittal craniosynostosis identified from population-based birth defects surveillance systems in New York State and in Iowa and will enroll unaffected controls identified from birth certificate data in each state. To improve characterization of sagittal NSC, we will collect detailed family history information from parents of index children and use advanced quantitative morphological tools to characterize and evaluate archived images to determine phenotypic variation between cases. To assess morbidity and mortality associated with surgical repair and by type of care setting within these well-defined phenotypic groups, we will use follow-up medical record abstraction. To identify genetic risk factors for sagittal NSC, we will collect improved biologic samples from the index child and birth parents to conduct candidate gene association studies, including replication of our preliminary findings of associations with a region on chromosome 3q. With the well-described phenotypes generated using family, medical, and surgical history and imaging analysis, we will explore the effects of modifiable risk factors, such as cigarette smoking, both independently and in combination with variants identified from our candidate gene analysis. In summary, this application proposes a multi-site phenotype and genotype study focused at determining the clinical, anthropometric, outcome, and molecular characteristics of defined subgroups of NSC. In addition, we will also identify genes associated with sagittal NSC and morphological criteria for diagnostic phenotyping. Our goals are to ascertain characterized patient populations, to identify areas for improved clinical care, and to maintain a database and sample repository available to the scientific community.